Studies of transfusion-associated hepatitis at NIH and of community- acquired hepatitis at CDC indicated that 10% to 20% of observed hepatitis cases could not be accounted for by the known hepatitis viruses: HAV, HBV, HCV, HDV, and HEV. To investigate the existence of an additional agent or agents of human hepatitis, a CRADA was established between the Department of Transfusion Medicine of NIH, Genelabs Technologies, Inc. of Emeryville, CA, and the CDC. Suspect clinical materials were sent to Genelabs, where they were amplified following reverse transcription by Sequence Independent Single Primer Amplification and then cloned into E. coli using a gt11 expression vector . A unique clone was identified that was novel to the gene bank and exogenous by hybridization assays. The agent could be recovered from the cloning source and was shown to be a flavivirus distinct from other members of that family. It had approximately 25% homology with HCV A polymerase chain reaction assay was developed and clinical materials screened. The agent, tentatively designated HGV, is associated with approximately 20% of transfusion and community-associated hepatitis that is unrelated to previously recognized agents, but its causal role in the development of hepatitis has not been established. HGV is found in 1 % to 2% of blood donors and has been proved to be transfusion-transmitted by linked donor-recipient samples. In summary, HGV is a new member of the Flaviviridae family that is prevalent in the general population and transfusion transmissible. Further studies are required to establish its disease burden and particularly, to define whether it causes hepatitis or is merely associated with hepatitis because of shared transmission patterns with another agent(s) that is currently undetectable.